Computer software for visualizing recombination events in a group of individuals from recombination breakpoints and assignments in high density SNP genotyping data by generating a color-coded view for each individual chromosome and a whole genome view for the group

ABSTRACT

A computer system for visualizing recombination events in a group of individuals is provided. According to one aspect of the invention, high-density SNP genotype data is obtained from related individuals in a family. A pedigree is created, haplotypes are reconstructed and likely recombination breakpoints are identified with the use of publicly available computer programs. A software tool is then used facilitate the visualization of the recombination events in the family.

RELATED APPLICATION

This application claims the benefit of U.S. provisional application60/773,282, filed on Feb. 14, 2006, which is herein incorporated byreference in its entirety for all purposes.

BACKGROUND OF THE INVENTION

The present invention relates to the field of computer systems. Morespecifically, the present invention relates to computer systems forvisualizing biological information. Devices and computer systems forforming and using arrays of materials on a substrate are known. Newgenotyping technologies, such as the Affymetrix SNP 100K and 500K assays(commercially available from Affymetrix, Inc., Santa Clara, Calif.94024, USA), have paved the way for large scale genotyping analysis.

SUMMARY OF THE INVENTION

An improved computer-aided system for visualizing and determininginformation is disclosed. In one aspect of the invention, a softwaretool (methods and computer software products) for visualizingrecombination events in families is provided. In a preferred embodiment,high-density SNP genotype data (e.g., 100k, 500k, MIP (targetedgenotyping) assays from Affymetrix, Illumina genotyping assays and anyother suitable genotyping methods including resequencing, de novosequencing) is obtained from related individuals in a family. A pedigreeis constructed based on the known relationships of the individuals. Acomputer software module, such as the publicly available Merlin, usesthe genotype and pedigree information to reconstruct haplotypes andidentify likely recombination breakpoints. A software tool is then usedto facilitate visualization. The visualization software can beillustrated using an exemplary embodiment, “Chromosome Painter” thattakes this information on recombination breakpoints and grandparentalassignment and color-codes the data for each chromosome so that it canbe visualized in color.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the high level flow of the method used to visualizerecombination events in families according to an embodiment of thepresent invention.

FIG. 2 illustrates a detail level flow of one implementation of thereference method according to an embodiment of the present invention.

FIG. 3 illustrates an example of a pedigree file.

FIG. 4 illustrates an example of a summary chromosome chart (Chromosome6) according to an embodiment of the present invention.

FIG. 5 illustrates an example of a whole genome view according to anembodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

A. General

The present invention has many preferred embodiments and relies on manypatents, applications and other references for details known to those ofthe art. Therefore, when a patent, application, or other reference iscited or repeated below, it should be understood that it is incorporatedby reference in its entirety for all purposes as well as for theproposition that is recited.

As used in this application, the singular form “a,” “an,” and “the”include plural references unless the context clearly dictates otherwise.For example, the term “an agent” includes a plurality of agents,including mixtures thereof.

An individual is not limited to a human being but may also be otherorganisms including but not limited to mammals, plants, bacteria, orcells derived from any of the above.

Throughout this disclosure, various aspects of this invention can bepresented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible subranges as well asindividual numerical values within that range. For example, descriptionof a range such as from 1 to 6 should be considered to have specificallydisclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from2 to 6, from 3 to 6 etc., as well as individual numbers within thatrange, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of thebreadth of the range.

The practice of the present invention may employ, unless otherwiseindicated, conventional techniques and descriptions of organicchemistry, polymer technology, molecular biology (including recombinanttechniques), cell biology, biochemistry, and immunology, which arewithin the skill of the art. Such conventional techniques includepolymer array synthesis, hybridization, ligation, and detection ofhybridization using a label. Specific illustrations of suitabletechniques can be had by reference to the example herein below. However,other equivalent conventional procedures can, of course, also be used.Such conventional techniques and descriptions can be found in standardlaboratory manuals such as Genome Analysis: A Laboratory Manual Series(Vols. I-IV), Using Antibodies: A Laboratory Manual, Cells: A LaboratoryManual, PCR Primer: A Laboratory Manual, and Molecular Cloning: ALaboratory Manual (all from Cold Spring Harbor Laboratory Press).Stryer, L. (1995) Biochemistry (4th Ed.) Freeman, New York, Gait,“Oligonucleotide Synthesis: A Practical Approach” 1984, IRL Press,London, Nelson and Cox (2000), Lehninger, Principles of Biochemistry,3^(rd) Ed., W. H. Freeman Pub., Pub., New York, N.Y. and Berg et al.(2002k) Biochemistry, 5^(th) Ed., W. H. Freeman Pub., New York, N.Y.,all of which are herein incorporated in their entirety by reference forall purposes.

The present invention can employ solid substrates, including arrays insome preferred embodiments. Methods and techniques applicable to polymer(including protein) array synthesis have been described in U.S. Ser. No.09/536,841, WO 00/58516, U.S. Pat. Nos. 5,143,854, 5,242,974, 5,252,743,5,324,633, 5,384,261, 5,405,783, 5,424,186, 5,451,683, 5,482,867,5,491,074, 5,527,681, 5,550,215, 5,571,639, 5,578,832, 5,593,839,5,599,695, 5,624,711, 5,631,734, 5,795,716, 5,831,070, 5,837,832,5,856,101, 5,858,659, 5,936,324, 5,968,740, 5,974,164, 5,981,185,5,981,956, 6,025,601, 6,033,860, 6,040,193, 6,090,555, 6,136,269,6,269,846 and 6,428,752, in PCT Applications Nos. PCT/US99/00730(International Publication No. WO 99/36760) and PCT/US01/04285(International Publication No. WO 01/58593), which are all incorporatedherein by reference in their entirety for all purposes.

Patents that describe synthesis techniques in specific embodimentsinclude U.S. Pat. Nos. 5,412,087, 6,147,205, 6,262,216, 6,310,189,5,889,165 and 5,959,098. Nucleic acid arrays are described in many ofthe above patents, but the same techniques are applied to polypeptidearrays.

Nucleic acid arrays that are useful in the present invention includethose that are commercially available from Affymetrix (Santa Clara,Calif.) under the brand name GeneChip®. Example arrays are shown on thewebsite at affymetrix.com.

The present invention also contemplates many uses for polymers attachedto solid substrates. These uses include gene expression monitoring,profiling, library screening, genotyping and diagnostics. Geneexpression monitoring and profiling methods can be shown in U.S. Pat.Nos. 5,800,992, 6,013,449, 6,020,135, 6,033,860, 6,040,138, 6,177,248and 6,309,822. Genotyping and uses therefore are shown in U.S. Ser. Nos.10/442,021, 10/013,598 (U.S. Patent Application Publication20030036069), and U.S. Pat. Nos. 5,856,092, 6,300,063, 5,858,659,6,284,460, 6,361,947, 6,368,799 and 6,333,179. Other uses are embodiedin U.S. Pat. Nos. 5,871,928, 5,902,723, 6,045,996, 5,541,061, and6,197,506.

The present invention also contemplates sample preparation methods incertain preferred embodiments. Prior to or concurrent with genotyping,the genomic sample may be amplified by a variety of mechanisms, some ofwhich may employ PCR. See, for example, PCR Technology: Principles andApplications for DNA Amplification(Ed. H. A. Erlich, Freeman Press, NewYork, N.Y., 1992); PCR Protocols: A Guide to Methods and Applications.(Eds. Innis, et al., Academic Press, San Diego, Calif. 1990); Mattila etal., Nucleic Acids Res. 19, 4967 (1991); Eckert et al., PCR Methods andApplications 1, 17 (1991); PCR (Eds. McPherson et al., IRL Press,Oxford); and U.S. Pat. Nos. 4,683,202, 4,683,195, 4,800,159, 4,965,188,and 5,333,675, and each of which is incorporated herein by reference intheir entireties for all purposes. The sample may be amplified on thearray. See, for example, U.S. Pat. No. 6,300,070 and U.S. Ser. No.09/513,300, which are incorporated herein by reference.

Other suitable amplification methods include the ligase chain reaction(LCR) (for example, Wu and Wallace, Genomics 4, 560(1989), Landegren etal., Science 241, 1077 (1988) and Barringer et al. Gene 89:117 (1990)),transcription amplification (Kwoh et al., Proc. Natl. Acad. Sci. USA 86,1173 (1989) WO 88/10315), self-sustained sequence replication (Guatelliet al., Proc. Nat. Acad. Sci. USA, 87, 1874 (1990) and WO 90/06995),selective amplification of target polynucleotide sequences (U.S. Pat.No. 6,410,276), consensus sequence primed polymerase chain reaction(CP-PCR) (U.S. Pat. No. 4,437,975), arbitrarily primed polymerase chainreaction (AP-PCR) (U.S. Pat. Nos. 5,413,909, 5,861,245) and nucleic acidbased sequence amplification (NABSA). (See, U.S. Pat. Nos.5,409,818,554,517, and 6,063,603, each of which is incorporated hereinby reference). Other amplification methods that may be used aredescribed in, U.S. Pat. Nos. 5,242,794, 5,494,810, 4,988,617 and in U.S.Ser. No. 09/854,317, each of which is incorporated herein by reference.

Additional methods of sample preparation and techniques for reducing thecomplexity of a nucleic sample are described in Dong et al., GenomeResearch 11, 1418 (2001), in U.S. Pat. No. 6,361,947, 6,391,592 and U.S.Ser. Nos. 09/916,135, 09/920,491 (U.S. Patent Application Publication20030096235), 09/910,292 (U.S. Patent Application Publication20030082543), and application Ser. No. 10/013,598.

Methods for conducting polynucleotide hybridization assays have beenwell developed in the art. Hybridization assay procedures and conditionswill vary depending on the application and are selected in accordancewith the general binding methods known including those referred to in:Maniatis et al. Molecular Cloning: A Laboratory Manual (2^(nd) Ed. ColdSpring Harbor, N.Y. 1989); Berger and Kimmel Methods in Enzymology, Vol.152, Guide to Molecular Cloning Techniques (Academic Press, Inc., SanDiego, Calif., 1987); Young and Davism, P.N.A.S, 80: 1194(1983). Methodsand apparatus for carrying out repeated and controlled hybridizationreactions have been described in U.S. Pat. Nos. 5,871,928, 5,874,219,6,045,996 and 6,386,749, 6,391,623 each of which are incorporated hereinby reference

The present invention also contemplates signal detection ofhybridization between ligands in certain preferred embodiments. See U.S.Pat. Nos. 5,143,854, 5,578,832; 5,631,734; 5,834,758; 5,936,324;5,981,956; 6,025,601; 6,141,096; 6,185,030; 6,201,639; 6,218,803; and6,225,625, in U.S. Ser. No. 10/389,194 and in PCT ApplicationPCT/US99/06097 (published as WO99/47964), each of which also is herebyincorporated by reference in its entirety for all purposes.

Methods and apparatus for signal detection and processing of intensitydata are disclosed in, for example, U.S. Pat. Nos. 5,143,854, 5,547,839,5,578,832, 5,631,734, 5,800,992, 5,834,758; 5,856,092, 5,902,723,5,936,324, 5,981,956, 6,025,601, 6,090,555, 6,141,096, 6,185,030,6,201,639; 6,218,803; and 6,225,625, in U.S. Ser. Nos. 10/389,194,60/493,495 and in PCT Application PCT/US99/06097 (published asWO99/47964), each of which also is hereby incorporated by reference inits entirety for all purposes.

The practice of the present invention may also employ conventionalbiology methods, software and systems. Computer software products of theinvention typically include computer readable medium havingcomputer-executable instructions for performing the logic steps of themethod of the invention. Suitable computer readable medium includefloppy disk. CD-ROM/DVD/DVD-ROM, hard-disk drive, flash memory, ROM/RAM,magnetic tapes and etc. The computer executable instructions may bewritten in a suitable computer language or combination of severallanguages. Basic computational biology methods are described in, forexample Setubal and Meidanis et al., Introduction to ComputationalBiology Methods (PWS Publishing Company, Boston, 1997); Salzberg,Searles, Kasif, (Ed.), Computational Methods in Molecular Biology,(Elsevier, Amsterdam, 1998); Rashidi and Buehler, Bioinformatics Basics:Application in Biological Science and Medicine (CRC Press, London, 2000)and Ouelette and Bzevanis Bioinformatics: A Practical Guide for Analysisof Gene and Proteins (Wiley & Sons, Inc., 2^(nd) ed., 2001). See U.S.Pat. No. 6,420,108.

The present invention may also make use of various computer programproducts and software for a variety of purposes, such as probe design,management of data, analysis, and instrument operation. See, U.S. Pat.Nos. 5,593,839, 5,795,716, 5,733,729, 5,974,164, 6,066,454, 6,090,555,6,185,561, 6,188,783, 6,223,127, 6,229,911 and 6,308,170.

Additionally, the present invention may have preferred embodiments thatinclude methods for providing genetic information over networks such asthe Internet as shown in U.S. Ser. Nos. 10/197,621, 10/063,559 (UnitedStates Publication No. 20020183936), Ser. Nos. 10/065,856, 10/065/868,10/328,818, 10/328,872, 10/423,403, and 60/482,389.

B. Definitions

The term “array” as used herein refers to an intentionally createdcollection of molecules which can be prepared either synthetically orbiosynthetically. The molecules in the array can be identical ordifferent from each other. The array can assume a variety of formats,for example, libraries of soluble molecules; libraries of compoundstethered to resin beads, silica chips, or other solid supports.

The term “biomonomer” as used herein refers to a single unit ofbiopolymer, which can be linked with the same or other biomonomers toform a biopolymer (for example, a single amino acid or nucleotide withtwo linking groups one or both of which may have removable protectinggroups) or a single unit which is not part of a biopolymer. Thus, forexample, a nucleotide is a biomonomer within an oligonucleotidebiopolymer, and an amino acid is a biomonomer within a protein orpeptide biopolymer, avidin, biotin, antibodies, antibody fragments,etc., for example, are also biomonomers.

The term “biopolymer” or sometimes refer by “biological polymer” as usedherein is intended to mean repeating units of biological or chemicalmoieties. Representative biopolymers include, but are not limited to,nucleic acids, oligonucleotides, amino acids, proteins, peptides,hormones, oligosaccharides, lipids, glycolipids, lipopolysaccharides,phospholipids, synthetic analogues of the foregoing, including, but notlimited to, inverted nucleotides, peptide nucleic acids, Meta-DNA, andcombinations of the above.

The term “biopolymer synthesis” as used herein is intended to encompassthe synthetic production, both organic and inorganic, of a biopolymer.Related to a biopolymer is a “biomonomer”.

The term “combinatorial synthesis strategy” as used herein refers to acombinatorial synthesis strategy is an ordered strategy for parallelsynthesis of diverse polymer sequences by sequential addition ofreagents which may be represented by a reactant matrix and a switchmatrix, the product of which is a product matrix. A reactant matrix is a1 column by m row matrix of the building blocks to be added. The switchmatrix is all or a subset of the binary numbers, preferably ordered,between 1 and m arranged in columns. A “binary strategy” is one in whichat least two successive steps illuminate a portion, often half, of aregion of interest on the substrate. In a binary synthesis strategy, allpossible compounds which can be formed from an ordered set of reactantsare formed. In most preferred embodiments, binary synthesis refers to asynthesis strategy which also factors a previous addition step. Forexample, a strategy in which a switch matrix for a masking strategyhalves regions that were previously illuminated, illuminating about halfof the previously illuminated region and protecting the remaining half(while also protecting about half of previously protected regions andilluminating about half of previously protected regions). It will berecognized that binary rounds may be interspersed with non-binary roundsand that only a portion of a substrate may be subjected to a binaryscheme. A combinatorial “masking” strategy is a synthesis which useslight or other spatially selective deprotecting or activating agents toremove protecting groups from materials for addition of other materialssuch as amino acids.

The term “complementary” as used herein refers to the hybridization orbase pairing between nucleotides or nucleic acids, such as, forinstance, between the two strands of a double stranded DNA molecule orbetween an oligonucleotide primer and a primer binding site on a singlestranded nucleic acid to be sequenced or amplified. Complementarynucleotides are, generally, A and T (or A and U), or C and G. Two singlestranded RNA or DNA molecules are said to be complementary when thenucleotides of one strand, optimally aligned and compared and withappropriate nucleotide insertions or deletions, pair with at least about80% of the nucleotides of the other strand, usually at least about 90%to 95%, and more preferably from about 98 to 100%. Alternatively,complementarity exists when an RNA or DNA strand will hybridize underselective hybridization conditions to its complement. Typically,selective hybridization will occur when there is at least about 65%complementary over a stretch of at least 14 to 25 nucleotides,preferably at least about 75%, more preferably at least about 90%complementary. See, M. Kanehisa Nucleic Acids Res. 12:203 (1984),incorporated herein by reference.

The term “effective amount” as used herein refers to an amountsufficient to induce a desired result.

The term “fragmentation” refers to the breaking of nucleic acidmolecules into smaller nucleic acid fragments. In certain embodiments,the size of the fragments generated during fragmentation can becontrolled such that the size of fragments is distributed about acertain predetermined nucleic acid length.

The term “genome” as used herein is all the genetic material in thechromosomes of an organism. DNA derived from the genetic material in thechromosomes of a particular organism is genomic DNA. A genomic libraryis a collection of clones made from a set of randomly generatedoverlapping DNA fragments representing the entire genome of an organism.

The term “hybridization” as used herein refers to the process in whichtwo single-stranded polynucleotides bind non-covalently to form a stabledouble-stranded polynucleotide; triple-stranded hybridization is alsotheoretically possible. The resulting (usually) double-strandedpolynucleotide is a “hybrid.” The proportion of the population ofpolynucleotides that forms stable hybrids is referred to herein as the“degree of hybridization.” Hybridizations are usually performed understringent conditions, for example, at a salt concentration of no morethan 1 M and a temperature of at least 25° C. For example, conditions of5×SSPE (750 mM NaCl, 50 mM NaPhosphate, 5 mM EDTA, pH 7.4) and atemperature of 25-30° C. are suitable for allele-specific probehybridizations. For stringent conditions, see, for example, Sambrook,Fritsche and Maniatis. “Molecular Cloning A laboratory Manual” 2^(nd)Ed. Cold Spring Harbor Press (1989) which is hereby incorporated byreference in its entirety for all purposes above.

The term “hybridization conditions” as used herein will typicallyinclude salt concentrations of less than about 1M, more usually lessthan about 500 mM and preferably less than about 200 mM. Hybridizationtemperatures can be as low as 5° C., but are typically greater than 22°C., more typically greater than about 30° C., and preferably in excessof about 37° C. Longer fragments may require higher hybridizationtemperatures for specific hybridization. As other factors may affect thestringency of hybridization, including base composition and length ofthe complementary strands, presence of organic solvents and extent ofbase mismatching, the combination of parameters is more important thanthe absolute measure of any one alone.

The term “hybridization probes” as used herein are oligonucleotidescapable of binding in a base-specific manner to a complementary strandof nucleic acid. Such probes include peptide nucleic acids, as describedin Nielsen et al., Science 254, 1497-1500 (1991), and other nucleic acidanalogs and nucleic acid mimetics.

The term “hybridizing specifically to” as used herein refers to thebinding, duplexing, or hybridizing of a molecule only to a particularnucleotide sequence or sequences under stringent conditions when thatsequence is present in a complex mixture (for example, total cellular)DNA or RNA.

The term “initiation biomonomer” or “initiator biomonomer” as usedherein is meant to indicate the first biomonomer which is covalentlyattached via reactive nucleophiles to the surface of the polymer, or thefirst biomonomer which is attached to a linker or spacer arm attached tothe polymer, the linker or spacer arm being attached to the polymer viareactive nucleophiles.

The term “isolated nucleic acid” as used herein mean an object speciesinvention that is the predominant species present (i.e., on a molarbasis it is more abundant than any other individual species in thecomposition). Preferably, an isolated nucleic acid comprises at leastabout 50, 80 or 90% (on a molar basis) of all macromolecular speciespresent. Most preferably, the object species is purified to essentialhomogeneity (contaminant species cannot be detected in the compositionby conventional detection methods).

The term “label” as used herein refers to a luminescent label, a lightscattering label or a radioactive label. Fluorescent labels include,inter alia, the commercially available fluorescein phosphoramiditiessuch as Fluoreprime (Pharmacia), Fluoredite (Millipore) and FAM (ABI).See U.S. Pat. No. 6,287,778.

The term “ligand” as used herein refers to a molecule that is recognizedby a particular receptor. The agent bound by or reacting with a receptoris called a “ligand,” a term which is definitionally meaningful only interms of its counterpart receptor. The term “ligand” does not imply anyparticular molecular size or other structural or compositional featureother than that substance in question is capable of binding or otherwiseinteracting with the receptor. Also, a ligand may serve either as thenatural ligand to which the receptor binds, or as a functional analoguethat may act as an agonist or antagonist. Examples of ligands that canbe investigated by this invention include, but are not restricted to,agonists and antagonists for cell membrane receptors, toxins and venoms,viral epitopes, hormones (for example, opiates, steroids, etc.), hormonereceptors, peptides, enzymes, enzyme substrates, substrate analogs,transition state analogs, cofactors, drugs, proteins, and antibodies.

The term “linkage disequilibrium” or sometimes refer by allelicassociation as used herein refers to the preferential association of aparticular allele or genetic marker with a specific allele, or geneticmarker at a nearby chromosomal location more frequently than expected bychance for any particular allele frequency in the population. Forexample, if locus X has alleles a and b, which occur equally frequently,and linked locus Y has alleles c and d, which occur equally frequently,one would expect the combination ac to occur with a frequency of 0.25.If ac occurs more frequently, then alleles a and c are in linkagedisequilibrium. Linkage disequilibrium may result from natural selectionof certain combination of alleles or because an allele has beenintroduced into a population too recently to have reached equilibriumwith linked alleles.

The term “mixed population” or sometimes refer by “complex population”as used herein refers to any sample containing both desired andundesired nucleic acids. As a non-limiting example, a complex populationof nucleic acids may be total genomic DNA, total genomic RNA or acombination thereof. Moreover, a complex population of nucleic acids mayhave been enriched for a given population but include other undesirablepopulations. For example, a complex population of nucleic acids may be asample which has been enriched for desired messenger RNA (mRNA)sequences but still includes some undesired ribosomal RNA (rRNA).

The term “monomer” as used herein refers to any member of the set ofmolecules that can be joined together to form an oligomer or polymer.The set of monomers useful in the present invention includes, but is notrestricted to, for the example of (poly)peptide synthesis, the set ofL-amino acids, D-amino acids, or synthetic amino acids. As used herein,“monomer” refers to any member of a basis set for synthesis of anoligomer. For example, dimers of L-amino acids form a basis set of 400“monomer” for synthesis of polypeptides. Different basis sets ofmonomers may be used at successive steps in the synthesis of a polymer.The term “monomer” also refers to a chemical subunit that can becombined with a different chemical subunit to form a compound largerthan either subunit alone.

The term “mRNA” or sometimes refer by “mRNA transcripts” as used herein,include, but not limited to pre-mRNA transcript(s), transcriptprocessing intermediates, mature mRNA(s) ready for translation andtranscripts of the gene or genes, or nucleic acids derived from the mRNAtranscript(s). Transcript processing may include splicing, editing anddegradiation. As used herein, a nucleic acid derived from an mRNAtranscript refers to a nucleic acid for whose synthesis the mRNAtranscript or a subsequence thereof has ultimately served as a template.Thus, a cDNA reverse transcribed from an mRNA, an RNA transcribed fromthat cDNA, a DNA amplified from the cDNA, an RNA transcribed from theamplified DNA, etc., are all derived from the mRNA transcript anddetection of such derived products is indicative of the presence and/orabundance of the original transcript in a sample. Thus, mRNA derivedsamples include, but are not limited to, mRNA transcripts of the gene orgenes, cDNA reverse transcribed from the mRNA, cRNA transcribed from thecDNA, DNA amplified from the genes, RNA transcribed from amplified DNA,and the like.

The term “nucleic acid library” or sometimes refer by “array” as usedherein refers to an intentionally created collection of nucleic acidswhich can be prepared either synthetically or biosynthetically andscreened for biological activity in a variety of different formats (forexample, libraries of soluble molecules; and libraries of oligostethered to resin beads, silica chips, or other solid supports).Additionally, the term “array” is meant to include those libraries ofnucleic acids which can be prepared by spotting nucleic acids ofessentially any length (for example, form 1 to about 1000 nucleotidemonomers in length) onto a substrate. The term “nucleic acid” as usedherein refers to a polymeric form of nucleotides of any length, eitherribonucleotides, deoxyribonucleotides or peptide nucleic acids (PNAs),that comprise purine and pyrimidine bases, or other natural, chemicallyor biochemically modified, non-natural, or derivatized nucleotide bases.The backbone of the polynucleotide can comprise sugars and phosphategroups, as may typically be found in RNA or DNA, or modified orsubstituted sugar or phosphate groups. A polynucleotide may comprisemodified nucleotides, such as methylated nucleotides and nucleotideanalogs. The sequence of nucleotides may be interrupted bynon-nucleotide components. Thus the terms nucleoside, nucleotide,deoxynucleoside and deoxynucleotide generally include analogs such asthose described herein. These analogs are those molecules having somestructural features in common with a naturally occurring nucleoside ornucleotide such that when incorporated into a nucleic acid oroligonucleoside sequence, they allow hybridization with a naturallyoccurring nucleic acid sequence in solution. Typically, these analogsare derived from naturally occurring nucleosides and nucleotides byreplacing and/or modifying the base, the ribose or the phosphodiestermoiety. The changes can be tailor made to stabilize or destabilizehybrid formation or enhance the specificity of hybridization with acomplementary nucleic acid sequence as desired.

The term “nucleic acids” as used herein may include any polymer oroligomer of pyrimidine and purine bases, preferably cytosine, thymine,and uracil, and adenine and guanine, respectively. See Albert L.Lehninger, PRINCIPLES OF BIOCHEMISTRY, at 793-800 (Worth Pub. 1982).Indeed, the present invention contemplates any deoxyribonucleotide,ribonucleotide or peptide nucleic acid component, and any chemicalvariants thereof, such as methylated, hydroxymethylated or glucosylatedforms of these bases, and the like. The polymers or oligomers may beheterogeneous or homogeneous in composition, and may be isolated fromnaturally-occurring sources or may be artificially or syntheticallyproduced. In addition, the nucleic acids may be DNA or RNA, or a mixturethereof, and may exist permanently or transitionally in single-strandedor double-stranded form, including homoduplex, heteroduplex, and hybridstates.

The term “oligonucleotide” or sometimes refer by “polynucleotide” asused herein refers to a nucleic acid ranging from at least 2, preferableat least 8, and more preferably at least 20 nucleotides in length or acompound that specifically hybridizes to a polynucleotide.Polynucleotides of the present invention include sequences ofdeoxyribonucleic acid (DNA) or ribonucleic acid (RNA) which may beisolated from natural sources, recombinantly produced or artificiallysynthesized and mimetics thereof. A further example of a polynucleotideof the present invention may be peptide nucleic acid (PNA). Theinvention also encompasses situations in which there is a nontraditionalbase pairing such as Hoogsteen base pairing which has been identified incertain tRNA molecules and postulated to exist in a triple helix.“Polynucleotide” and “oligonucleotide” are used interchangeably in thisapplication.

The term “polymorphism” as used herein refers to the occurrence of twoor more genetically determined alternative sequences or alleles in apopulation. A polymorphic marker or site is the locus at whichdivergence occurs. Preferred markers have at least two alleles, eachoccurring at frequency of greater than 1%, and more preferably greaterthan 10% or 20% of a selected population. A polymorphism may compriseone or more base changes, an insertion, a repeat, or a deletion. Apolymorphic locus may be as small as one base pair. Polymorphic markersinclude restriction fragment length polymorphisms, variable number oftandem repeats (VNTR's), hypervariable regions, minisatellites,dinucleotide repeats, trinucleotide repeats, tetranucleotide repeats,simple sequence repeats, and insertion elements such as Alu. The firstidentified allelic form is arbitrarily designated as the reference formand other allelic forms are designated as alternative or variantalleles. The allelic form occurring most frequently in a selectedpopulation is sometimes referred to as the wildtype form. Diploidorganisms may be homozygous or heterozygous for allelic forms. Adiallelic polymorphism has two forms. A triallelic polymorphism hasthree forms. Single nucleotide polymorphisms (SNPs) are included inpolymorphisms.

The term “primer” as used herein refers to a single-strandedoligonucleotide capable of acting as a point of initiation fortemplate-directed DNA synthesis under suitable conditions for example,buffer and temperature, in the presence of four different nucleosidetriphosphates and an agent for polymerization, such as, for example, DNAor RNA polymerase or reverse transcriptase. The length of the primer, inany given case, depends on, for example, the intended use of the primer,and generally ranges from 15 to 30 nucleotides. Short primer moleculesgenerally require cooler temperatures to form sufficiently stable hybridcomplexes with the template. A primer need not reflect the exactsequence of the template but must be sufficiently complementary tohybridize with such template. The primer site is the area of thetemplate to which a primer hybridizes. The primer pair is a set ofprimers including 5′ upstream primer that hybridizes with the 5′ end ofthe sequence to be amplified and a 3′ downstream primer that hybridizeswith the complement of the 3′ end of the sequence to be amplified.

The term “probe” as used herein refers to a surface-immobilized moleculethat can be recognized by a particular target. See U.S. Pat. No.6,582,908 for an example of arrays having all possible combinations ofprobes with 10, 12, and more bases. Examples of probes that can beinvestigated by this invention include, but are not restricted to,agonists and antagonists for cell membrane receptors, toxins and venoms,viral epitopes, hormones (for example, opioid peptides, steroids, etc.),hormone receptors, peptides, enzymes, enzyme substrates, cofactors,drugs, lectins, sugars, oligonucleotides, nucleic acids,oligosaccharides, proteins, and monoclonal antibodies.

The term “receptor” as used herein refers to a molecule that has anaffinity for a given ligand. Receptors may be naturally-occurring ormanmade molecules. Also, they can be employed in their unaltered stateor as aggregates with other species. Receptors may be attached,covalently or noncovalently, to a binding member, either directly or viaa specific binding substance. Examples of receptors which can beemployed by this invention include, but are not restricted to,antibodies, cell membrane receptors, monoclonal antibodies and antiserareactive with specific antigenic determinants (such as on viruses, cellsor other materials), drugs, polynucleotides, nucleic acids, peptides,cofactors, lectins, sugars, polysaccharides, cells, cellular membranes,and organelles. Receptors are sometimes referred to in the art asanti-ligands. As the term receptors is used herein, no difference inmeaning is intended. A “Ligand Receptor Pair” is formed when twomacromolecules have combined through molecular recognition to form acomplex. Other examples of receptors which can be investigated by thisinvention include but are not restricted to those molecules shown inU.S. Pat. No. 5,143,854, which is hereby incorporated by reference inits entirety.

The term “solid support”, “support”, and “substrate” as used herein areused interchangeably and refer to a material or group of materialshaving a rigid or semi-rigid surface or surfaces. In many embodiments,at least one surface of the solid support will be substantially flat,although in some embodiments it may be desirable to physically separatesynthesis regions for different compounds with, for example, wells,raised regions, pins, etched trenches, or the like. According to otherembodiments, the solid support(s) will take the form of beads, resins,gels, microspheres, or other geometric configurations. See U.S. Pat. No.5,744,305 for exemplary substrates.

The term “target” as used herein refers to a molecule that has anaffinity for a given probe. Targets may be naturally-occurring orman-made molecules. Also, they can be employed in their unaltered stateor as aggregates with other species. Targets may be attached, covalentlyor noncovalently, to a binding member, either directly or via a specificbinding substance. Examples of targets which can be employed by thisinvention include, but are not restricted to, antibodies, cell membranereceptors, monoclonal antibodies and antisera reactive with specificantigenic determinants (such as on viruses, calls or other materials),drugs, oligonucleotides, nucleic acids, peptides, cofactors, lectins,sugars, polysaccharides, cells, cellular membranes, and organelles.Targets are sometimes referred to in the art as anti-probes. As the termtargets is used herein, no difference in meaning is intended. A “ProbeTarget Pair” is formed when two macromolecules have combined throughmolecular recognition to form a complex.

C. Embodiments

Synthesized nucleic acid probe arrays, such as Affymetrix GeneChip®probe arrays, and spotted arrays, have been used to generateunprecedented amounts of information about biological systems. Forexample, the GeneChip® Human Genome U133 Pus 2.0 Array available fromAffymetrix, Inc. of Santa Clara, Calif., is comprised of one microarraycontaining 1,300,000 oligonucleotide features covering more than 47,000transcripts and variants that include 38,500 well characterized humangenes. Other examples of GeneChip® arrays are targeted to provide dataaimed at different areas of specialization. Examples of specialized usesinclude analysis of Single Nucleotide Polymorphisms (SNPs) provided bythe GeneChip® Human Mapping 10K, 100K, or 500K Arrays, or analysis ofalternative splicing events provided by the GeneChip® Human Exon 1.0 STArray or analysis of detecting germ line and deterplasmic mutationsprovided by the GeneChip® Human Mitochondrial REsequencing Array 2.0.Analysis of data from such microarrays may lead to the development ofnew drugs and new diagnostic tools.

In one aspect of the invention, a software tool (methods and computersoftware products) for visualizing recombination events in families isprovided. FIG. 1 illustrates a high level flow of an example of themethod used to visualize recombination events in families. This diagramis merely an example, which should not unduly limit the scope of theclaims. One of ordinary skill in the art would recognize manyvariations, alternatives, and modifications. At step 201, in a preferredembodiment, high-density SNP genotyping data (e.g., 100k, 500k, MIP(targeted genotyping) assays from Affymetrix, Illumina genotyping assaysand any other suitable genotyping methods including resequencing, denovo sequencing) is obtained from related individuals in a family. Atstep 202, a pedigree is constructed based on the known relationships ofthe individuals. A pedigree file can contain information about familyrelationships and other characteristics, for example, gender and geneticdata (disease and marker phenotypes). The pedigree file can be used todescribe individuals which include people, animals, plants, insects,etc. In the preferred embodiment, pedigree files are created from agroup of individuals where high-density SNP genotyping data can beobtained. There are several software tools that are available to createpedigree files, for example, Pedigree Drawing Tool from Progeny, PED 5Pedigree Drawing Software from Medgen, CircuSoft OPEDiT pedigree drawingsoftware from CircuSoft Instrumentation, etc. FIG. 3 illustrates anexample of a pedigree file according to an embodiment of the presentinvention. This diagram is merely an example, which should not undulylimit the scope of the claims. One of ordinary skill in the art wouldrecognize many variations, alternatives, and modifications. In thisexample, there are two sets of grandparents: Paternal (PGM(paternalgrandmother) and PGP(paternal grandpa)) and MGM(maternal grandmother)and MGP(maternal grandpa), father, mother and a child. Other examplesmay include great grandparents, aunts, uncles, cousins, step parent,step child, cousins, etc.

At step 203, a computer software module, such as the publicly availableMerlin (Abecasis et al., Nat Genet. 30:97-101 (2002) and Nicolae et al,MERLIN . . . and the Geneticist's Stone?, Nature Genetics, 30, 3-4(2002)), uses the genotype and pedigree information to reconstructhaplotypes and identify likely recombination breakpoints. At step 204, asoftware tool is then used to facilitate visualization, for example,color-codes data for each chromosome, pattern-codes data for eachchromosome, physical shape pop out data for each chromosome, sound-codesdata for each chromosome, etc. The visualization software can beillustrated using an exemplary preferred embodiment, “ChromosomePainter” that takes this information on recombination breakpoints andgrandparental assignment and color-codes the data for each chromosome sothat it can be visualized in color. At step 205, the visualrecombination events in the families are provided. The form of thevisualization can be of various chart types, for example, line, column,stacked column, floating column, 3D column, Stack 3D column, Parallel 3Dcolumn, pie, 3D pie, bar, stacked bar, floating bar, area, stacked area,scatter, polar, mixed, etc. Other forms of visualization can be data inthe form of links within the charts or graphs. For example, the linkscan open up and display detailed data or information regarding thecorresponding area. One of ordinary skill in the art would recognizemany variations, alternatives, and modifications.

In one aspect genotyping data is obtained using molecular inversionprobe technology as described, for example, in U.S. Pat. No. 6,858,412and in Hardenbol et al., Genome Res. 15:269-275 (2005).

In another aspect, genotype data is obtained from high densitygenotyping arrays such as mapping arrays and resequencing arrays.Mapping arrays are commercially available from Affymetrix, Inc., forexample, the Mapping 10K, Mapping 100K and Mapping 500K array sets, andhave been described for example, in U.S. Patent Publication Nos.20040146890, 20060024715, 20050227244 and 20050142577. Methods for usingmapping arrays are disclosed, for example, in Kennedy et al., Nat.Biotech. 21:1233-1237 (2003), Matsuzaki et al., Genome Res. 14:414-425(2004). Matsuzaki et al., Nat. Meth. 1:109-111 (2004) and U.S. PatentPub. Nos. 20040146890 and 20050042654. Resequencing arrays, arecommercially available from Affymetrix, Inc. and have been described,for example, see Cutler, D. J. et al., Genome Res. 11(11), 1913-25,2001.

Computer implemented methods for determining genotype using data frommapping arrays are disclosed, for example, in Liu, et al.,Bioinformatics 19:2397-2403 (2003) and Di et al., Bioinformatics21:1958-63 (2005). Computer implemented methods for linkage analysisusing mapping array data are disclosed, for example, in Ruschendorf andNurnberg, Bioinformatics 21:2123-5 (2005) and Leykin et al., BMC Genet.6:7, (2005).

Methods of determining haplotypes are disclosed, for example, in U.S.patent publication 20030170665. For a discussion of haplotype structuresee also Lindblad-Toh et al., Nature 438:803-19 (2005) and Walsh et al.,Am J. Hum. Genet. 73:580-90 (2003). For a discussion of methods forinferring haplotype phase from genotype data see, for example, Marchiniet al., Am J Hum Genet 78:437-450 (2006). All cited references areincorporated herein by reference in their entireties for all purposes.

In one aspect of the present invention, FIG. 2 illustrates a furtherdetailed view of the instructions for an exemplary preferred processflow of the method used to visualize recombination events in families.This diagram is merely an example, which should not unduly limit thescope of the claims. One of ordinary skill in the art would recognizemany variations, alternatives, and modifications. The visualizationsoftware can be illustrated using an exemplary embodiment, “ChromosomePainter” that takes this information on recombination breakpoints andgrandparental assignment and color-codes the data for each chromosome sothat it can be visualized in color. In a preferred embodiment, the Linux(software platform) system is used to generate the files and the Windowsystem is used to generate the input files and the final plots. Inanother preferred embodiment, the programs: GDAS (GeneChip DNA AnalysisSoftware, available from Affymetrix, Inc.), R scripts, Shell scripts,Perl scripts and Merlin software program are used to visualizerecombination events in families.

In a preferred embodiment, the following Step-by step instructions areprovided:

-   -   1. Obtain high-density SNP genotyping data. This can be obtained        by the various technologies mentioned above (ie. GeneChip® Human        Mapping 100 k arrays) as indicated in step 201. Use a compatible        DNA software analysis tool (i.e. GDAS) to export the CHP files        to the format of the software program that can create a pedigree        file (i.e. Merlin formats), including DAT files, PED files and        the genetic map files. (specify the file names as zsf_*.dat,        zsf_.map, zsf_.ped and separate them by chromosomes).        -   A. Create a pedigree file for the samples as indicated in            step 202.        -   B. Click “Run”-→AttributeImporter Tool, browse to input the            pedigree file        -   C. Specify template “pedigree”, and the project name “ZSF”        -   D. In DM window, click “tools”→“genotype”→“linkage export”.    -   2. Open the map file, delete those SNPs with genetic map 0.    -   3. Choose a folder on the chosen software platform (i.e. Linux        System) for this project. Ftp the files (dat files, map file and        ped files) to your folder on Linux system using text mode. Also        ftp the following files under S:/CHUN/ZANDER/program/to the        folder: splitmap.R, hapzsf.sh, alignhap.pl, sorthapout.pl,        recomfunc.R sumhaptrunk.R, chranno_*.txt. Text mode is        recommended in ftp process. Note: chranno_*.txt need to be        prepared beforehand according to annotation files on the current        genome build (including chromosome, SNPID, physical locations        and genetic locations). Splitanno.R is the R script used to        split an assembled annotation file (anno35_sorted.map was        prepared by manually editing the annotation file from NetAFFX)        by chromosomes.    -   4. Under Linux system, under your folder, type the following        command lines:        -   mv zsf_X_(—)01.dat zsf_(—)23.dat        -   mv zsf_X_(—)01.ped zsf_(—)23.ped    -   5. At step 301, the map file is split by chromosomes by typing        the command line (note to change the name of the map file,        modify the script)        -   source/nfs/share/env/R-1.9.0.env (recommend: put in            bash_profile before you log on)        -   R BATCH splitmap.R tmp.out &    -   6. At step 302, a computer software module (i.e. Merlin)        estimates the haplotypes and the recombination patterns in the        family by typing the command line:        -   source /nfs/share/env/merlin-0.10.2.env (recommend: put in            bash_profile before you log on)        -   chmod+x hapzsf.sh        -   ./hapzsf.sh (note: the names of the dat file, ped file and            map file are hard-coded in the script, modify the script            when needed. Output file zsfhap_chr*.txt for each            chromosome)    -   7. At step 303, a software tool (i.e. Merlin) is used to align        the SNPs with their chromosomal positions and reformat the        haplotype outputs by typing the command line:        -   perl alignhap.pl (note the name of the map files and the            outputs from Merlin are hard-coded, output files            zsfhap_*.out for each chromosome)    -   8. Sort the SNPs by the physical locations:        -   perl sorthapout.pl (output files: sortedhap_*.out for each            chromosome)    -   9. At step 304, the recombination patterns are summarized        according to the output by running R scripts:        -   R BATCH recomfunc.R tmp.out &        -   R BATCH sumhaptrunk.R tmp.out &    -   10. Ftp files (with the names as: lucas_m_chr1.txt,        lucas_p_chr1.txt, etc.) to Windows, make sure you have R        installed on your machine.    -   11. physchr.txt is required for this step. This file indicates        the start and stop physical locations for each chromosome.        Current version fits for Mapping 100K. Open R, change the        working directory to the folder with all the transferred files,        run script plothap.R. The colored family tree for all the 23        chromosomes will be generated automatically to the current        working folder. The file names are: family_chr*.eps for each        chromosome (23 in total).    -   12. At step 305, a summary file for each person in the family        (dadsum.txt, auntsum.txt, etc.) and a whole genome view for the        family are generated by running the script plotgenome.R. The        format of the summary file: each row stands for one chromosome;        there are 4 columns in total, each column stands for number of        maternal recombinations in this chromosome; the mean length of        the haplotype blocks in this chromosome; number of paternal        recombination in this chromosome; the mean length of the        haplotype blocks in this chromosome.

FIG. 4 illustrates an example of a chromosome summary chart according toa preferred embodiment of the present invention: FIG. 4 shows a chartfor Chromosome 6. This diagram is merely an example, which should notunduly limit the scope of the claims. One of ordinary skill in the artwould recognize many variations, alternatives, and modifications. FIG. 5illustrates an example of a whole genome view of a family according toanother embodiment of the present invention. This diagram is merely anexample, which should not unduly limit the scope of the claims. One ofordinary skill in the art would recognize many variations, alternatives,and modifications.

According to an embodiment of the present invention, a computer programmethod for visualizing recombination events in a group of individuals isprovided which includes a computer code that receives a plurality highdensity SNP genotyping data and a computer code that generates apedigree file from the genotyping data. Additionally, the methodincludes a computer code that receives haplotype and recombinationpattern data generated from a computer program that uses the genotypingdata and pedigree file to reconstruct the haplotypes and identify therecombination patterns. Moreover, the method includes a computer codethat generates the visualization of recombination events in the group ofindividuals and a computer readable medium that stores the computercodes. In a preferred embodiment, the plurality high density SNPgenotyping data are generated from microarrays.

In one aspect of the present invention, the computer program methodprovides a color-coded view for each individual chromosome. In anotherpreferred embodiment, the computer program method provides a color-codedwhole genome view. According to another embodiment of the presentinvention, the computer program method for visualizing recombinationevents can be from a family, a village, a country, a population, or anyother group of individuals.

According to yet another embodiment of the present invention, a systemthat visualizes recombination evens in a group of individuals isprovided which includes a processor, and a computer readable mediumcoupled to the processor for storing a computer program. The storedcomputer program includes a computer code that receives a plurality highdensity SNP genotyping data, a computer code that generates a pedigreefile from the genotyping data, a computer code that receives haplotypeand recombination pattern data generated from a computer program thatuses the genotyping data and pedigree file to reconstruct the haplotypesand identify the recombination patterns, and a computer code thatgenerates the visualization of recombination events in the group ofindividuals. In a preferred embodiment, the plurality high density SNPgenotyping data are generated from microarrays. In another preferredembodiment, the computer program method provides a color-coded view foreach individual chromosome. In yet another preferred embodiment, thecomputer program method provides a color-coded whole genome view.According to another embodiment of the present invention, the computerprogram method for visualizing recombination events can be from afamily, a village, a country, a population, or any other group ofindividuals.

EXAMPLE Example 1

DNA samples from individuals in a family are collected and tested withGeneChip® Human Mapping 100K microarrays. FIG. 2 outlines the steps thatare taken to visualize recombination events in the family. As indicatedin step 201, GDAS (GeneChip DNA Analysis Software, available fromAffymetrix, Inc.) is used to analyze the high-density SNP genotypingdata generated from using the 100K microarrays. GDAS is used to exportthe CHP files to Merlin-format, including DAT files, PED files and thegenetic map files. At step 202, a pedigree file is created. An exampleof a pedigree file that can be generated is illustrated in FIG. 3. Inthis family, there are 2 sets of grandparents: PGM (paternalgrandmother), PGP (paternal grandpa) and MGM (maternal grandmother), MGP(maternal pa). This study also includes the Mom, Dad, and a child.

To prepare for the next step, the map file is opened, and those SNPswith genetic map “0” are deleted. A folder on the Linux System(softwareplatform) for this project is chosen. The files (dat files, map file andped files) are Ftp'd to the folder on the Linux system by using the textmode. In addition, the following files are placed underS:/CHUN/ZANDER/program/ to the folder: splitmap.R, hapzsf.sh,alignhap.pl, sorthapout.pl, recomfunc.R sumhaptrunk.R, chranno_*.txt.The following command lines are typed: “mv zsf_X_(—)01.datzsf_(—)23.dat” and “mv zsf_X_(—)01.ped zsf_(—)23.ped” under the Linuxsystem, under the operating folder.

At step 301, the file names are specified as zsf_*.dat, zsf_.map,zsf_.ped and the map files are separated by chromosomes by typing thecommand line “source /nfs/share/env/R-1.9.0.env”.

At step 302, the computer software module, Merlin is used to estimatethe haplotypes and the recombination patterns in the family. Thehapoltypes and gene flow are estimated by typing the command line:“source /nfs/share/env/merlin-0.10.2. env” and “chmod+x hapzsf.sh./hapzsf.sh”.

At step 303, the computer software module, Merlin is used to align theSNP ID and physical locations with the Output from Merlin. The SNPs arealigned with their chromosomal positions and the haplotype outputs arereformatted: “perl alignhap.pl”. The SNPs are sorted by their physicallocations: “perl sorthapout.pl”.

At step 304, the recombination patterns are summarized by running Rscripts: “R BATCH recomfunc.R tmp.out &” and “R BATCH sumhaptrunk.Rtmp.out &”. Double crossovers within 5 Mb are removed. The files areFtp'd to Windows and R is verified to be installed on the machine.Physchr.txt, the version which fits for Mapping 100K, is installed. R isopened and the working directory is changed to the folder with all thetransferred files, and the script plothap.R is performed.

At step 305, a color-coded view for each individual chromosome summaryfile for each person in the family and a whole genome view for thefamily are generated by running script plotgenome.R. Chromosome summarycharts for the individual Chromosomes (1-23) are generated for theindividuals in the family. FIG. 4, a summary chart for Chromosome 6, isan example of what a summary chromosome chart may look like. The summarychromosome chart provides another way to visualize the data on how eachindividual is related. In this example, as shown in FIG. 4, the PGM iscoded with red and green lines. The PGP is coded with dark blue andturquoise lines, MGM is coded with pink and yellow lines, and the MGP iscoded with grey and black lines. In this example, the color(s) of thefirst line indicates related data from the mother side and the color(s)from the second line indicates related data from the father side. Instudying this family tree, one can trace the inheritance of a giventrait in the family. Factors that are involved in determining patternsof inheritance include the location of the trait-causing gene. Thesefactors can be visually observed in the summary chromosome charts. Toobtain a view of all the chromosomes for each person in the family, thewhole genome view charts are generated for the family. FIG. 5 is anexample of what a whole genome view for a family may look like.

The above description is illustrative and not restrictive. Manyvariations of the invention will become apparent to those of skill inthe art upon review of this disclosure. Merely by way of example, whilethe invention is illustrated with particular reference to the evaluationof DNA (natural or unnatural), the methods can be used in the analysisfrom chips with other materials synthesized thereon, such as RNA. Thescope of the invention should, therefore, be determined not withreference to the above description, but instead should be determinedwith reference to the appended claims along with their full scope ofequivalents.

1. A computer program stored on a non-transitory computer readablemedium that when executed visualizes recombination events in a group ofindividuals, comprising: computer code that receives a plurality of highdensity SNP genotyping data; computer code that generates a pedigreefile from the genotyping data; computer code that receives haplotype andrecombination pattern data generated from a computer program that usesthe genotyping data and pedigree file to reconstruct the haplotypes andidentify the recombination patterns, wherein the recombination patternsis a plurality of recombination breakpoints and assignments; andcomputer code that generates the visualization of recombination eventsin the group of individuals, wherein a color-coded view for eachindividual chromosome and a whole genome view for the group ofindividuals are generated.
 2. The computer program of claim 1 whereinthe visualization of recombination events is a color-coded view for eachindividual chromosome.
 3. The computer program of claim 1 wherein thevisualization of recombination events is a color-coded whole genomeview.
 4. The computer program of claim 1 wherein the group ofindividuals is a population.
 5. A computer program stored on anon-transitory computer readable medium that when executed visualizesrecombination events in a group of individuals, comprising: computercode that receives a plurality of high density SNP genotyping data,wherein the plurality of high density SNP genotyping data is generatedfrom microarrays; computer code that generates a pedigree file from thegenotyping data; computer code that receives haplotype and recombinationpattern data generated from a computer program that uses the genotypingdata and pedigree file to reconstruct the haplotypes and identify therecombination patterns; and computer code that generates thevisualization of recombination events in the group of individuals. 6.The computer program of claim 5 wherein the group of individuals is afamily.
 7. The computer program of claim 5 wherein the group ofindividuals is a village.
 8. The computer program of claim 5 wherein thegroup of individuals is a country.
 9. A system that visualizesrecombination events in a group of individuals, comprising: a processor;and a computer readable storage medium coupled to the processor forstoring a computer program comprising: computer code that receives aplurality of high density SNP genotyping data; computer code thatgenerates a pedigree file from the genotyping data; computer code thatreceives haplotype and recombination pattern data generated from acomputer program that uses the genotyping data and pedigree file toreconstruct the haplotypes and identify the recombination patternswherein the recombination patterns are a plurality of recombinationbreakpoints and a plurality of assignments; and computer code thatgenerates the visualization of recombination events in the group ofindividuals, wherein a color-coded view for each individual chromosomeand a whole genome view for the group of individuals are generated. 10.A system according to claim 9 wherein the group of individuals is apopulation.
 11. A system that visualizes recombination events in a groupof individuals, comprising: a processor; and a computer readable storagemedium coupled to the processor for storing a computer programcomprising: computer code that receives a plurality of high density SNPgenotyping data wherein the plurality of high density SNP genotypingdata is generated from microarrays; computer code that generates apedigree file from the genotyping data; computer code that receiveshaplotype and recombination pattern data generated from a computerprogram that uses the genotyping data and pedigree file to reconstructthe haplotypes and identify the recombination patterns; and computercode that generates the visualization of recombination events in thegroup of individuals.
 12. A system according to claim 11 wherein thegroup of individuals is a family.
 13. A system according to claim 11wherein the group of individuals is a village.
 14. A system according toclaim 11 wherein the group of individuals is a country.
 15. A method ofvisualizing recombination events in a group of individuals, comprising:providing a computer with a computer readable storage medium comprisingcomputer usable code comprising: computer code for receiving a pluralityof high density SNP genotyping data; computer code for generating apedigree file from the genotyping data; computer code for receivinghaplotype and recombination pattern data generated from a computerprogram that uses the genotyping data and pedigree file to reconstructthe haplotypes and identify the recombination patterns; and computercode for generating the visualization of recombination events in thegroup of individuals.
 16. The method of claim 15 wherein the pluralityof high density SNP genotyping data is generated from microarrays. 17.The method of claim 15 wherein the visualization of recombination eventsis a color-coded view for each individual chromosome.
 18. The method ofclaim 15 wherein the visualization of recombination events is acolor-coded whole genome view.
 19. The method of claim 15 wherein thegroup of individuals is a family.
 20. The method of claim 15 wherein thegroup of individuals is a village.
 21. The method of claim 15 whereinthe group of individuals is a country.
 22. The method of claim 15wherein the group of individuals is a population.